POS0417 LESS ACPA EPITOPE EXPANSION IS FOUND IN ACPA-POSITIVE IMMUNE CHECKPOINT INHIBITOR ARTHRITIS PATIENTS COMPARED TO ACPA-POSITIVE RHEUMATOID ARTHRITIS PATIENTS
Authors: D. Rajesh, N. Ghosh, J. Kirschmann, K. K. Chan, D. Jannat-Khah, S. Goodman, V. Bykerk, W. Robinson, A. Bass
Journal: Annals of the Rheumatic Diseases (2022)

Background Immune checkpoint inhibitors (ICI) have markedly improved the treatment of many advanced cancers; however, they can result in immune-related adverse events (irAE) including ICI arthritis (ICI-A). ICI-A often resembles rheumatoid arthritis (RA) and ~9% of ICI-A patients are anti-citrullinated peptide antibody (ACPA) positive. In RA, ACPA epitope expansion occurs over the years prior to onset of clinical disease. In this study we examined the degree of ACPA epitope expansion in seropositive ICI-A patients in order to determine whether it is similar to early RA, or more suggestive of the pre-clinical phase of disease 1 . Objectives To compare the number of ACPA epitopes targeted in seropositive ICI-A versus RA. Methods We used clinical data and serum from 12 ACPA+ ICI-A patients enrolled in a prospective registry and 39 ACPA+ RA patients enrolled in the CATCH-US early RA cohort. ACPA screening was done using a commercial ELISA (positive &gt;20 units/mL). A custom, bead-based antigen array was used to identify antibody reactivities to 16 putative RA associated citrullinated proteins. Synovial fluid (SF) samples from 3 of the ICI-A patients were also tested using the bead-based microarray. Hierarchical clustering software was used to create heatmaps to identify ACPA levels. Z-scores for fluorescence intensity were also calculated separately for each peptide, and a fluorescence level above the mean (Z-score&gt;0) was defined as a positive ACPA. The number of positive epitopes for each patient was determined and compared categorically between the ICI-A and RA patients using Fischer’s exact test. Results Characteristics of ICI-A and early RA patients are listed in Table 1. Compared to RA patients, ICI-A patients were older (mean 71 years vs. 48 years), more likely to have ever smoked (67% vs. 36%) and less likely to have positive rheumatoid factor (RF) (8% vs. 69%). Median symptom duration for ICI-A patients was 3.7 months compared to 6.7 months in RA patients. The median ACPA titer was lower in ICI-A patients than RA patients (42 units/mL vs. 250 units/mL). As demonstrated in Figure 1, lower signal intensities (level of ACPA) and a lower number of distinct ACPA epitopes were seen in the serum of ICI-A patients compared to RA patients. Of ICI-A patients, 67% were positive for 0-4 ACPA epitopes, 8% for 5-10 epitopes and 25% for &gt;10 epitopes, as opposed to 23% of RA patients positive for 0-4 epitopes, 36% for 5-10 epitopes, and 41% for &gt;10 epitopes (p=0.02). The one ICI-A patient who was also RF positive had 12 positive ACPA epitopes. There was no significant difference in the number of ACPA epitopes in ICI-A patients who were smokers vs. nonsmokers, RA-like vs. PMR-like, or who received ICI combination vs. ICI monotherapy. In the 3 ICI-A patients with synovial fluid samples, SF ACPA was not demonstrated. Table 1. Baseline Characteristics of ACPA+ ICI-A and RA Patients ICI-A (N=12) Early RA (N=39) Age in years, mean (SD ) 71.0 (8.3) 48.2 (14.6) Female Sex 7 (58%) 33 (85%) White/Caucasian 9 (75%) 27 (69%) Symptom Duration in months, median [IQR] 3.7 [1.0,11.3] 6.7 [4.0,9.7] RF Positive 1 (8%) 27 (69%) ACPA level (units/mL), median [IQR] 42.2 [29.4,70.5] 250 [107.5,251.0] Obese (BMI≥30 ) 3 (25%) 9 (23%) Current/Past Smoker 8 (67%) 14 (36%) Cancer Type ǂ Melanoma 4 (33%) Renal Cell Carcinoma 3 (25%) ICI Regimen PD-1/PD-L1 7 (58%) CTLA-4+PD-1 5 (42%) ICI-A Phenotype RA-like 9 (75%) PMR-like 3 (25%) ǂ Other cancer types in ICI-A patients included urothelial carcinoma (n=2), non-small cell lung cancer (n=2), and head and neck cancer (n=1). Figure 1. Heat Map of ACPA repertoire in RA Patients and ICI-A Patients. Conclusion ICI-A patients had lower ACPA titers and targeted fewer ACPA epitopes than early RA patients. It remains to be determined if ICI-A represents an accelerated model of RA pathogenesis with ICI triggering an early transition from pre-clinical to clinical disease. This would require sequential sampling and analysis. References [1]Sokolove J. et al. PLoS One. 2012;7(5)e35296 Disclosure of Interests Diviya Rajesh: None declared, Nilasha Ghosh: None declared, Jessica Kirschmann: None declared, Karmela Kim Chan: None declared, Deanna Jannat-Khah Shareholder of: AstraZeneca, Walgreens, and Cytodyn, Susan Goodman Consultant of: UCB Data Monitoring and Safety Board, Grant/research support from: Novartis, Vivian Bykerk Consultant of: Amgen, Bristol Myers Squibb, Genzyme, Gilead, Janssen, Pfizer, Sanofi-Aventis, and UCB, Grant/research support from: Bristol Myers Squibb, Amgen, and The Cedar Hill Foundation, William Robinson: None declared, Anne Bass: None declared.